The GABAergic system of the mammalian brain consists of neurons that release GABA and receptors that bind GABA. The GABA-releasing cells are extraordinarily diverse and highly specialized. Some GABAergic cells control the activity in a local network (interneurons, INs), while others constitute the output of a well-defined structure (e.g., striatal medium spiny neurons, MSNs). The receptors for GABA are also diverse and specific. Ligand-gated GABA receptors (GABAARs), members of the Cys-loop receptor family, are present on virtually every neuron in the brain and perform different functions depending on their synaptic or extrasynaptic localization. The GABAARs located outside the synapses (peri- or extrasynaptically) are activated by GABA molecules present in the extracellular space. These GABAARs mediate a type of inhibition that is "always on", also termed tonic inhibition. The studies completed during the past funding period have addressed fundamental mechanisms related to the nature, pharmacology and origin of tonic inhibition. As a direct continuation of the research carried out during the previous funding period, the present project will focus on novel and untested roles of the tonic GABA conductance in cellular/network excitability and neuroprotection. The proposal will address a specific hypothesis using state-of-the-art electrophysiological, microscopical, molecular pharmacological, optical, and transgenic mouse technologies. The hypothesis posits that a tonically active GABAAR-mediated conductance is essential for protecting highly vulnerable neurons in the brain against hyperexcitability and neurotoxicity. The aim is to focus on two damage-prone brain regions where this conductance is present, but can be altered under various conditions. The proposed studies will elucidate the mechanisms whereby the tonic GABA conductance dampens excessive synchrony in the hyperexcitable hippocampal CA3 region and how it protects neostriatal neurons against neurotoxicity. Considering the extremely excitable nature of the CA3 region and its relevance to epilepsy, and the high susceptibility of the neostriatum to dysfunction and degeneration, these experiments will address central issues related to the pathologies and treatments of epilepsies, Huntington's disease (HD), Tourette's syndrome (TS) and other disorders of the limbic system and striatum. The studies are expected to generate novel pharmacological interventions specific for tonic inhibition for the treatment of disorders related to neuronal synchrony including epilepsy and cognitive disorders, and for treating or preventing neurodegenerative conditions of the striatum and other damage-prone brain structures. PUBLIC HEALTH RELEVANCE The principal inhibitory neurotransmitter in the mammalian brain is 3-aminobutyric acid (GABA). The GABAergic system of the brain can be disrupted at the level of the nerve cells that produce and release GABA or at the level of the receptors that are activated by the transmitter. Both disruptions have devastating effects on the brain's normal functioning. The present proposal will address critical aspects of the GABAergic signaling in health and disease. It will tackle the role of a special type of neuronal communication, characterized during our previous funding period, involving the actions of GABA molecules that float around in the extracellular space of the brain. Such ambient levels of GABA can effectively and uninterruptedly control the excitability of a large number of neurons. Receptors activated during this sustained (tonic) type of inhibition are the specific targets of important modulatory compounds both endogenous (such as ovarian- and sex-hormone derivatives) and exogenous (such as ethanol) to the brain. The present proposal will address the role of this tonic form of inhibition in controlling neuronal network oscillations known to be important in epilepsy and cognitive function. Moreover it will examine the role of tonic inhibition in the first line of defense against the degeneration of striatal neurons known as a hallmark of Huntington's disease and other striatal dysfunction possibly involved in Parkinson's disease, Tourette syndrome and drug addiction. Our research shall reveal fundamental and novel mechanisms of GABA action, thus opening new and specific ways to defend nerve cells against hyperexcitability in epilepsy, degeneration in Huntington's disease and in other neurological disorders. Our findings will also help advance a new concept of striatal function, a part of the brain involved in movement disorders such as Parkinson's disease and Tourette syndrome, and in drug addiction.